Current nanotechnological approaches for an effective delivery of bio-active drug molecules in the treatment of acne

Abstract

Acne is a chronic inflammatory human skin disease, characterized by areas of skin with seborrhoea, comedones, papules, nodules, pimples, and possibly scarring with lesions occurring on face, neck, and back. Nanotechnological approaches such as particulate (solid lipid nanoparticles and microspheres), vesicular (liposomes and niosomes), colloidal drug delivery systems (micro-emulsion and nano-emulsion), and miscellaneous systems (aerosol foams and micro-sponges) have an important place in acne therapy. These approaches have an enormous opportunity for the designing of a novel, low-dose and effective treatment systems to control acne disease. In this review, we specially focus on the different nanotechnological approaches for an effective treatment of acne.

Keywords::

• acne vulgaris
• fullerenes
• liposomes
• micro-sponge
• Propionibacterium acnes

Introduction

Acne vulgaris (also known as simply acne) is a chronic inflammatory human skin disease, characterized by areas of skin with seborrhoea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), nodules (large papules), pimples, and possibly scarring with lesions occurring on face, neck, and back. The swollen glands form pink papules, encircled by comedones from pustules or cysts initiated by anxiety, hereditary factors, hormones, and bacteria that is, Propionibacterium acnes (P. acnes; Kim and Mancini 2013). Acne arises due to the action of hormones on the sebaceous glands of skin leads to persevering of the pores with sebum and eruptions of the lesions called pimples or zits, and it follows as a result of extreme sebum production together with epidermal hyperproliferation. Acne affects approximately 650 million people or about 9.4% of the population globally. It affects almost 90% of people during their teenage years due to an increase in testosterone hormone level and sometimes persists into adulthood (Tanghetti 2013). It is slightly more common in females than males (9.8% vs. 9.0%, respectively). In those over 40 years old, 1% of males and 5% of females still have problems. Acne affects 40–50 million people in the United States (16%) and approximately 3–5 million in Australia (23%). Acne has been classified into four major categories such as comedonal, papular, pustular, and severe pustulocystic acne (Patwardhan et al. 2013). Table I shows characteristics of various grade of acne.

Table I. Characteristics of various grade of acne.

Acne grade	Characteristics of acne
Comedonal acne	• Consist of comedones only. • Less than about 10 on the face. • None on the trunk. • No scaring and non-inflammatory in nature. • Comedones that are 1 mm or larger are called micro comedones.
Papular acne	• Consist of 10–25 papules on the face and trunk with mild scarring. • The presence of inflammatory lesions (less than 5 mm in diameter). • Papular acne is caused due to bacteria, oil, dirt and heat. • Mostly found on the face, back and posterior parts.
Pustular acne	• It is a subset of acne vulgaris. • Pustules are small bumps on the skin that fill with fluid or pus. • Consists of more than 25 pustules with moderate scarring. • These bumps can form on any part of the body, but they are most common on the back, neck, chest, and face.
Severe pustulocystic acne	• Consist of nodules or cysts with extensive scarring. • Inflammatory lesions over 5 mm in diameter. • Extensive nodules and cysts. • Appear on the buttocks, groin, and armpit area, and anywhere else where sweat collects in hair follicles and perspiration ducts. • Cystic acne affects deeper skin tissue than does common acne.

Causes of acne (Well 2013)

Various factors such as environmental factors (humidity, heat, etc.), emotional factors, hormonal factors (Androgenic progestin), and micro-organisms are mainly responsible for causing acne.

• High humidity, heat and other conditions cause recurrent and elongated sweating can aggravate acne.

• Tight fitting clothes that confine air movement and avoid evaporation of skin moisture contribute to acne.

• Exposure to grime, cooking oils/smoke or industrial chemicals such as petroleum derivatives can cause occupational acne.

• Hair sprays can block the pilosebaceous gland cause acne.

• Products that contain comedogenic oils cause acne due to occlusive and plugging the follicles.

• Emotional factors will not cause acne but it subsidizes to acne together with severe or prolonged periods of stress or other emotional extremes.

• Androgenic progestin and oral contraceptives are contributors to acne.

• Some medications can exacerbate preexisting acne such as corticosteroids, androgens, azathioprine, bromides with a high progestin level, isoniazid, lithium, phenytoin, and thyroid preparations.

• Acne vulgaris is mainly caused by gram-positive, non-spore forming, micro-aerophilic and rod-like bacterium P. acnes.

Pathogenesis of acne (Williams et al. 2012, Lolis et al. 2009, Pauli and Reunala 1987)

Acne is associated to hormones, sebum, follicle fallout, bacteria, and inflammation which initiate in the pilosebaceous units of the dermis. The major factors that cause acne include:

1. Increased sebum production: The one of the most important factors involved in the development of acne lesions is increased rate of sebum production. One imaginable role of sebum in the pathogenesis of acne is its primary or associative role in comedogenesis as well as providing the substrate for P. acnes growth. Figure 1 shows the basic mechanism involved in pathogenesis of acne.

2. Follicular hyper keratinization: Hindrance of the pilosebaceous canal heads the expansion of acne lacerations. The hindrance is produced by the growth of supporter keratinized cells within the channel that form an impaction blocking the flow of sebum. It may also be due to an irregularity in the sebaceous lipids resulting in a relative hyper proliferation of corneocytes. Comedones formation may be due to a localized deficiency of linoleic acid in pilosebaceous duct.

3. Abnormal bacterial function: Skin surface in acne disposed to areas are colonized with Staphylococcus epidermidis and P. acnes. P. acnes subsidize to inflammation through stimulation of various chemotactic factors and separation the comedones. Figure 2 shows the sequence of events leading to acne inflammation primarily induced by P. acnes.

Figure 1. Role of androgen involved in pathogenesis of acne.

Figure 2. Basic mechanism of acne induction by P. acne.

Various approaches for acne treatment

Topical approach (Fu and Vender 2011)

Topical therapy is active as first-line treatment in mild acne. Topical therapy along with systemic therapy control moderate and severe acne. Drugs employed for topical application are shown in Table II.

Table II. Topical drug for acne treatment.

Topical drug	Mechanism of action/Advantages	Adverse effects
Topical retinoid (Tretinoin, Adapalene, Tazarotene, Isotretinoin, Metretinide)	Target the micro comedo precursor lesion of acne. Target the abnormal follicular epithelial hyper proliferation, reduces follicular plugging, micro comedones, non-inflammatory and inflammatory acne lesion.	Irritant dermatitis, erythema, scaling, burning sensation
Topical antibiotics (Clindamycin, Erythromycin, Clarithromycin, Azithromycin, Nadifloxacin)	Inhibit the growth of P. acne and reduce inflammation. Topical antibiotics such as erythromycin and clindamycin are the most popular in the management of acne.	Erythema, peeling, itching, dryness, burning, bacterial resistance, cross resistance
New agents (Clindamycin, Benzoyl peroxide, Tretinoin)	Prevent and eliminate the development of P. acne resistance. Reducing both inflammatory and non-inflammatory acne lesions.	Skin irritation, burning, erythema, peeling, dryness, skin sensitivity
Herbal agents (Azelaic acid, Tea tree oil)	Effective for mild-to-moderate acne when applied topically at a 20% concentration. Act as antimicrobial, anti-inflammatory, and antioxidant.	Skin irritation

Systemic approach (Bettoli et al. 2010)

Systemic therapy is active as first-line treatment in moderate and severe acne along with topical therapy. Drugs employed for systemic application are shown in Table III.

Table III. Systemic drug for acne treatment.

Systemic drug	Mechanism of action/Advantages	Adverse effects
Systemic antibiotics (Tetracycline, Doxycycline, Minocycline, Erythromycin, Azithromycin)	Inhibit the growth of P. acne and reduce inflammation. Mainly moderate-to-severe inflammatory acne. Tetracycline's and derivatives still remain the first choice.	Gastrointestinal upset, vaginal candidiasis, pigment deposition in the skin & teeth
Hormonal therapy (Spironolactone, Flutamide, Cyproterone acetate)	Prevent the effects of androgens on the sebaceous gland and probably follicular keratinocytes	Hyperkalaemia, menstrual irregularities

Novel approach

Novel drug delivery strategies play an essential role in refining the topical delivery of anti-acne agents by enhancing their dermal localization with a concomitant reduction in their side effects. Pointing is the capability to direct the drug-loaded system to the site of attention. Controlled drug release and following biodegradation are important for developing successful formulations (Castro and Ferreira 2008). Potential releases mechanisms involve desorption of surface-bound/adsorbed drugs, diffusion through the carrier matrix, carrier matrix erosion, or combined erosion/ diffusion process. Novel carriers are gaining wide acceptance, which include utilization of carriers such as niosomes, liposome, emulsomes, transferosomes, micro emulsion, nano emulsion, and nano lipid carriers that are efficient to transfer the drug across the skin (Garg et al. 2013; Figure 3).

Figure 3. Novel approaches for acne treatment.

The main advantages of nanocarriers are:

• excellent entrapment efficiency;

• maintain the physiochemical properties of entrapped drug;

• act as penetration enhancers;

• act as local depot for sustained release of drugs;

• deliver the drug molecule to target site without effecting the normal organ or tissue;

• minimize the toxic effects;

• accommodate drug molecules with a wide range of solubility;

• accommodate both lipophilic and hydrophilic drugs;

• provide protection from hydrolysis and oxidation;

• provide rapid and efficient penetration of the drug moiety;

• increase the rate and extent of absorption of the drug;

• increase the residence time of drugs; and

• improve the horny layer properties.

Novel drug delivery systems used for acne treatment include:

Particulate systems

Solid lipid nanoparticles. Solid lipid nanoparticle (SLN) fabrication by the purpose of topical usage should be made up of lipids that remain in solid state at skin (32°C) and room temperature. Its particle surface is protected by a surfactant which stabilizes the dispersion. The major advantages are providing protection of labile compounds against chemical degradation as well as producing controlled release of the active ingredients. SLN with a drug-enriched shell shows burst release characteristics whereas SLN with a drug-enriched core leads to sustained release. SLN has occlusive assets, that is, they can be used in direction to increase the water content of the skin (Fireman et al. 2011). Raza et al. (2013) systematically optimized biocompatible isotretinoin (ITR)-loaded SLNs for topical treatment of all types of acne, including recalcitrant, severe and nodulocystic. The developed system was characterized and evaluated for skin compliance, skin transport characteristics and anti-acne potential against testosterone-induced acne in male Laca mice. The results showed that SLNs were able to transport the drug to various skin layers effectively while formed drug micro-reservoirs. The optimized SLNs exhibited drug entrapment of 89.49 ± 4.1% and showed marked anti-acne potential as well as tolerability on the mouse skin as compare the marketed product. The results assure massive promise of the optimized SLNs of ITR in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation (Raza et al. 2013).

Microspheres. Microsphere technology improves the treatment tolerability, encourage adherence, and contribute to better long-term therapeutic outcomes. Microsphere technology removes the quick delivery of high concentrations of active drug to the application site and instead facilitates controlled release of potentially irritating drugs. It is associated with improved treatment outcomes and minimal irritation. Microsphere formulations of topical Tretinoin and benzoyl peroxide (BPO) currently on the market have demonstrated good efficacy and tolerability and are expected to encourage adherence and long-term therapeutic benefit (Kircik 2011). Eichenfield et al. (2012) studied the safety and efficacy of Tretinoin microsphere gel (TMG) 0.04% pump in children aged 9–11 years with acne vulgaris. The results showed that greater improvement in the least-squares mean change in non-inflammatory lesions with TMG 0.04% than with vehicle (− 19.9 vs. − 9.7, p = 0.04) and a significant difference in Investigator Global Assessment of improvement at Week 12 between the children treated with TMG 0.04% pump and those treated with vehicle (p = 0.02), but there were no discernible differences in static acne severity scales. This study confirmed statistically significant differences in the reduction of non-inflammatory lesions between TMG 0.04% pump and vehicle in patients aged 9–11 years with acne vulgaris (Eichenfield et al. 2012).

Vesicular systems

Nowadays, vesicular systems, both liposomes and niosomes, play an increasingly important role in drug delivery as they can reduce drug toxicity and modify drug pharmacokinetics and bioavailability.

Liposomes. Liposomes are recurrently used as vehicles in pharmaceuticals and cosmetics for a controlled and optimized delivery to particular skin layers. Liposomes are spherical vesicles whose membrane consists of amphiphillic lipids (i.e., lipids that are hydrophilic on one side and lipophilic on the other side) that enclose an aqueous core, similar to the bilayer membranes of living cells. Because of the amphiphillic nature of liposomes, they may encapsulate both hydrophilic as well as lipophilic drugs. This unique dual release capability enables the delivery of two types of substances once they are applied on the skin; each differs in its effects on skin permeability, which may enhance the desired therapeutic benefit (Parnami et al. 2013). Pornpattananangkul et al. (2013) developed and evaluated of liposomal lauric acids (LipoLA) as an effective and safe therapeutic agent for the treatment of acne infection. It was observed that the resulting LipoLA readily fuse with bacterial membranes, causing effective killing of P. acnes by disrupting bacterial membrane structures. Topically applying LipoLA in a gel form onto the infectious sites leads to eradication of P. acnes bacteria in vivo. Further skin toxicity studies showed that LipoLA does not induce acute toxicity to normal mouse skin within 24 h. These results suggested that LipoLA hold a high therapeutic potential for the treatment of acne infection and other P. acnes-related diseases (Pornpattananangkul et al. 2013).

Niosomes. Niosomes appear as an interesting drug delivery system in the treatment of dermatological disorders especially for acne. In fact, topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. They are assumed to increase the horny layer properties, both by reducing trans-epidermal water loss and by increasing smoothness via replenishing lost skin lipids (Garg et al. 2012). Liu and Huang (2013) developed lipid vehicles to deliver curcumin and inhibit P. acnes in the skin. The inhibitory activities of the curcumin-containing vehicles against P. acnes were studied using the bioluminescence assay. Curcumin (0.43 μg/mL) in the vehicles significantly inhibited the growth of P. acnes. The formation of curcumin reservoir in the skin through the curcumin-loaded vehicles is confirmed using confocal laser scanning microscopy. Curcumin-loaded vehicles could efficiently accumulate in the skin and inhibit P. acnes in vitro. Our results highlight the potential of using vehicles containing lauric acid and curcumin as an alternative treatment for acne vulgaris (Liu and Huang 2013).

Colloidal dispersions

Surfactant-free emulsions. Emulsifier-free formulations are a developing area for dermatologic and cosmetic products. Most skin care products are emulsions, that is, a mixture of two or more materials that are not miscible with each other. As a result, they require the addition of surfactants (emulsifiers) that stabilize the formulation and increase its shelf life. Furthermore, once these surfactant agents are applied on the skin, they tend to emulsify and remove the natural lipids of the epidermis. Accordingly, the pharmaceutical industry has been developing surfactant-free emulsions as alternatives to conventional formulations using stabilizers, such as polymeric emulsifiers or solid particles. These stabilizers produce sufficiently stable products with a cosmetically pleasant appearance (Dominguez-Delgado et al. 2011). Dominguez-Delgado et al. (2011) prepared and characterized surfactant-free emulsions of Triclosan intended to be used for the treatment of acne. Differential scanning calorimetry, transmission electron microscopy, and scanning electron microscopy studies suggested that Triclosan-loaded emulsions show good encapsulation efficiency (95.9%). Emulsions, being free of surfactants or other potentially irritant agents, can be a good option for the delivery of Triclosan to the skin, representing a good alternative for the treatment of acne (Dominguez-Delgado et al. 2011).

Micro-emulsion. These are translucent mixtures of oil, surfactant, co-surfactant, and water, in which either the oil globules are dispersed in water (o/w) or water globule are dispersed in oils (w/o). Various studies have discovered the significance of micro-emulsion for dermal and transdermal delivery both in-vitro and in-vivo. Due to the high solubilization capacity, a large quantity of drug can be incorporated in this formulation. The components of microemulsion can interact with the lipid layers of stratum corneum and changes its structural integrity leading to enhance transdermal permeation of drug (Kumar et al. 2011). Liu and Huang (2012) studied the antimicrobial activity of curcumin-loaded myristic acid micro-emulsions against Staphylococcus epidermidis. Curcumin distribution in neonate pig skin was visualized using confocal laser scanning microscopy. Curcumin (0.86 μg/mL) in the myristic acid micro-emulsion could inhibit 50% of the bacterial growth, which was 12 times more effective than curcumin dissolved in dimethyl sulfoxide (DMSO). The cocktail combination of myristic acid and curcumin in the micro-emulsion carrier synergistically inhibited the growth of S. epidermidis (Liu and Huang 2012).

Nano-emulsion. Nano-emulsions (NEs) can also be defined as “ultrafine emulsions” because of the formation of droplets in the submicron range. A nano-emulsion seems to be transparent and translucent with a bluish color. The small-size droplets give them characteristic stability against creaming, sedimentation, flocculation, and coalescence. It allows the effective transport of active ingredients to the skin (Borges et al. 2013). Lin et al. (2013) developed lipid nanocarriers, NEs, and nanostructured lipid carriers (NLCs) that combine Tretinoin and tetracycline for the efficient topical delivery to treat acne vulgaris. The antibacterial activities of the nanosystems against Staphylococcus aureus, Pseudomonas aeruginosa, and P. acnes were evaluated using an agar diffusion assay. NEs and NLCs exhibited high entrapment of Tretinoin which ranged 60–100%. This is the first report examining skin permeation and antibacterial activities of dual-drug nanocarriers for acne treatment (Lin et al. 2013).

Miscellaneous systems

Aerosols foams. Aerosol foams have converted an increasingly standard type of topical formulation for a variety of skin conditions including acne vulgaris. The vehicle base of the foam can have a liquid or semi-solid consistency that shares the same physicochemical characteristics of conventional vehicles like creams, lotions, and gels, but it maintains desirable properties such as moisturizing, fast-drying effects, or higher drug bioavailability. The aerosol base is dispensed through a gas pressurized can that discharges the foam. The product characteristics (i.e., texture, bubble size and thickness, viscosity, stability, and spreadibility) are determined by the type of formulation and the dispensing container that are selected to suit the specific treatment needs (Simonart 2012). Del Rosso (2009) successfully prepared sodium sulfacetamide 10%-sulfur 5% emollient foam in the treatment of acne vulgaris. Recently, an emollient foam sodium sulfacetamide 10%-sulfur 5% formulation indicated for topical therapy of acne vulgaris, rosacea, and seborrhea dermatitis has become available (Del Rosso 2009).

Microsponges. Microsponges are biologically inert particles prepared of synthetic polymers with the capacity to store a volume of an active agent up to their own weight. Additionally, the particles assist to defend the entrapped active compound from physical and environmental degradation. The microsponge technology can be utilized in a variety of formulations, but is more frequently manufactured as gels. Once applied on the skin, microsponges slowly release the active agents (Jelvehgari et al. 2006). Jelvehgari et al. (2006) developed microsponge delivery system of BPO for the treatment of acne and athletes foot. The micrograph of microsponges showed that they were spherical in shape and contained pores. One of the research studies showed that an increase in the ratio of drug: polymer resulted in a reduction in the release rate of BPO from microsponges which were attributed to a decreased internal porosity of the microsponges (Jelvehgari et al. 2006).

Fullerenes. Fullerenes (resemble a hollow sphere) are molecules composed entirely of carbon. Once fullerenes come into contact with the skin, they migrate through the skin intracellularly, as opposite to affecting over cells. So, a fullerene could be used to “trap” active compounds and then release them into the epidermis on the skin after the application. Moreover, fullerenes, themselves, are thought to be potentially potent antioxidants (Inui et al. 2011). Inui et al. (2012) developed polyhydroxylated fullerene (capable of potent radical-scavenging activity) and investigated its inhibitory effects in vitro on sebum production in hamster sebocytes and in P. acnes lipase activity. These results suggested that fullerene could be a beneficial skin care reagent for controlling acne vulgaris by suppressing sebum in the inflammatory response and by reducing P. acnes lipase activity (Inui et al. 2012).

Table IV shows the various applications of novel nano-carrier systems in the effective treatment of acne.

Table IV. Applications of nano-carrier systems for treatment of acne.

Nano-carrier	Bioactive molecule	Results/Applications
Solid lipid nanoparticles	Isotretinoin (ITR)	Increasing the therapeutic performance of all types of acne, including recalcitrant, severe and nodulocystic (Raza et al. 2013).
Solid lipid nanoparticles	Tretinoin (TRE)	Increase the therapeutic effectiveness of drug for treatment of various skin diseases including acne and psoriasis (Ridolfi et al. 2012).
Solid lipid nanoparticles	Retinoic acid	Reduce skin irritation without reducing efficacy, for the topical treatment of acne (Castro et al. 2011).
Solid lipid nanoparticles	All-trans retinoic acid (RA)	Improve the entrapment efficiency of RA in SLN using a low surfactant/lipid ratio (Castro et al. 2007).
Solid lipid nanoparticles	Tretinoin (TRE)	Increase the therapeutic effectiveness of drug for treatment of various skin diseases including acne (Shah et al. 2009).
Microspheres	Adapalene	Improve the therapeutic index of drug for the treatment of acne (Rolland et al. 1993).
Microspheres	Tretinoin (TRE)	Showed excellent safety and efficacy of drug for the treatment of acne in the preadolescent population (Eichenfield et al. 2012).
Microspheres	Tretinoin (TRE)	Showed anti-inflammatory effects against acne after oral administration of Isotretinoin (Vender 2012).
Microspheres	Tretinoin (TRE)	Tretinoin gel microsphere 0.1% showed better cutaneous tolerability profile (Lucky and Sugarman 2011).
Microspheres	Tretinoin (TRE)	Showed greater therapeutic efficiency against mild-to-moderate acne (Leyden et al. 2009).
Liposomes	Clindamycin	Showed therapeutic effectiveness acne vulgaris in pig ear skin (Honzak and Sentjurc 2000).
Liposomes	Benzoyl peroxide (BPO)	Showed a significantly greater antibacterial efficacy for Propionibacteria and Micrococca-ceae (Fluhr et al. 1999).
Liposomes	Tretinoin (TRE)	Allows reduction of the concentration of the active agent without a decline in efficacy for acne vulgaris (Schafer-Korting et al. 1994).
Liposomes	5-aminolevulinic acid (5-ALA)	Reduced inflammatory facial acne in Asians, with a low risk of persistent phototoxic effects (Yeung et al. 2011).
Liposomes	5-aminolevulinic acid (ALA)	Improved inflammatory acne with minimal side effects in Asians (An et al. 2011).
Niosomes	Isotretinoin	Great potential for skin targeting, prolonging drug release, reduction of photo degradation, reducing skin irritation and improving topical delivery of drug (Kaur et al. 2010).
Niosomes	Curcumin	Curcumin-loaded vehicles could efficiently accumulate in the skin and inhibit P. acnes (Liu and Huang 2013).
Micro-emulsion	Thai basil oil, Holi basil oil	Showed therapeutic activity against P. acnes (Viyoch et al. 2006).
Nano-emulsion	Adapalene, Clindamycin	Showed more efficacious and better tolerated for the treatment of acne vulgaris in Indian patients (Prasad et al. 2012).
Aerosols foams	Povidone iodine	Act as skin cleanser in the management of acne vulgaris (Brown 1977).
Micro sponge	Tretinoin (TRE)	Showed an excellent treatment of face acne vulgaris (Leyden et al. 2002).
Fullerenes	Fullerenol C60(OH)44	Beneficial skin care reagent for controlling acne vulgaris by suppressing sebum in the inflammatory response and by reducing P. acnes lipase activity (Inui et al. 2012).
Fullerenes	Fullerenes	Fullerene gel help in controlling acne vulgaris with skin care benefit (Inui et al. 2011).

Conclusion

In this review, we have discussed about the whole global consequence of the disease by familiarizing drug delivery systems or by modifying the current ones as chemotherapy regimen for acne. Particulate, vesicular, and colloidal drug delivery approaches have their important place in acne therapy. From the above study, we can conclude that the above nanotechnology approaches has an enormous opportunity for the designing of a novel, low-dose and effective treatment systems to control acne disease. From the future perception, development of vaccines using combined strategic approach like nanocarriers can play a major role in the treatment of acne.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.